Cis-regulatory circuitry underlying hedgehog mediated limb development

摘要： Hedgehog（Hh）信号通路是器官发育的主要调节器，其利用初级的 纤毛通过GLI转录因子调控其转录输出。Hh信号的作用 主要是通过GLI靶基因的去抑制介导的，在没有Hh的情况下， 通过一种未知的机制进行转录。该提案旨在了解GLI阻遏物如何 在正常发育中调节Hedgehog信号传导，以及在纤毛病中如何改变。我们假设 GLI阻遏物通过调节增强子处的染色质修饰来抑制基因表达。我们将 确定GLI抑制是否通过组蛋白脱乙酰酶复合物的募集发生。我们还将 确定何时GLI增强子首次获得可接近的染色质以及它们与启动子的相互作用 需要Hh信令。我们进一步假设GLI蛋白在Hh之前抑制增强子活性， activation.通过测试，我们将提供关于早期Hh形态原的第一个详细信息 反应，并确定GLI转录动力学是否在人类纤毛病变的小鼠模型中改变。 总的来说，这些目标将提供关键的洞察力的过程和时间动态， 蛋白质与染色质相互作用并调节染色质以抑制转录。此外，他们将决定如何 GLI转录网络首先在纤毛病变中建立和改变， 失调导致这些综合征的结构性出生缺陷。

Abstract: The Hedgehog (Hh) signaling pathway is a major regulator of organ development that utilizes the primary cilium to regulate its transcriptional output through the GLI transcription factors. The effects of Hh signaling are primarily mediated through de-repression of GLI target genes, which in the absence of Hh inhibit transcription through an unknown mechanism. This proposal seeks to understand how GLI repressors regulate Hedgehog signaling in normal development and how this is altered in ciliopathies. We hypothesize that GLI repressors inhibit gene expression by regulating chromatin modifications at enhancers. We will determine if GLI repression occurs through the recruitment of a Histone deacetylase complex. We will also establish when GLI enhancers first acquire accessible chromatin and if their interactions with promoters require Hh signaling. We further hypothesize that GLI proteins repress enhancer activity prior to Hh activation. By testing this, we will provide the first detailed information about the early Hh morphogen response and determine if GLI transcriptional dynamics are altered in a mouse model of human ciliopathies. Collectively, these aims will provide key insights into the processes and temporal dynamics by which GLI proteins interact with and regulate chromatin to repress transcription. In addition, they will determine how GLI transcriptional networks are first established and altered in ciliopathies, providing insight into how GLI dysregulation causes structural birth defects in these syndromes.